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Bronchodilators COPD Therapeutic Class Review (TCR)

June 7 2011

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The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group any state Pharmacy and Therapeutics committee any state Medicaid Agency or any other clinical committee This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient medical professional or layperson seeking information about a specific course of treatment for a specific medical condition All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician andor other medical professional in regard to the best course of treatment for their specific medical condition This publication inclusive of all forms contained herein is intended to be educational in nature and is intended to be used for informational purposes only Send comments and suggestions to PSTCREditormagellanhealthcom

Bronchodilators COPD Review

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FDA-APPROVED INDICATIONS

Drug Manufacturer Indication(s)

albuterolipratropium inhalation solution

(Duoneb )1

generic For the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) in patients requiring more than one bronchodilator

albuterolipratropium MDI (Combivent )

2

Boehringer-Ingelheim For use in patients with COPD on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and require a second bronchodilator

ipratropium inhalation

solution (Atrovent )3

generic For maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema


aerosol MDI (Atrovent HFA)4

Boehringer-Ingelheim As a bronchodilator for maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema

roflumilast (DalirespTM)5 Forest Laboratories As a treatment to reduce the risk of COPD exacerbations in

patients with severe COPD associated with chronic bronchitis and a history of exacerbations

tiotropium inhalation powder DPI (Spiriva

Handihaler )6

Boehringer-Ingelheim For the long-term once-daily maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema

To reduce COPD exacerbations

MDI=metered-dose inhaler

DPI=dry powder inhaler

OVERVIEW

In the United States chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality7 COPD is a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema The airflow obstruction is generally progressive may be accompanied by airway hyperreactivity and may be partially reversible8

Although the precise distinctions between chronic bronchitis and emphysema are a subject of debate tradition holds that chronic bronchitis is responsible for 85 percent of COPD9 Patients with chronic bronchitis experience intermittent airway inflammation and excessive mucus production that leads to frequent prolonged episodes of productive cough In contrast 15 percent of patients with COPD suffer primarily from emphysema Emphysema is a disease in which destruction of the infrastructure of alveoli and distal airspaces and thus the portion of the lung that provides gas exchange and elastic recoil occurs10 The loss of alveolar walls results in decreased ventilation and a loss of the capillary network essential to perfusion

Both chronic bronchitis and emphysema predispose patients to a common constellation of symptoms and to a collection of derangements in respiratory function There are reductions in forced expiratory volume after one second (FEV1) forced vital capacity (FVC) FEV1FVC ratio and forced expiratory flow (FEF25-75) The 2009 revised Executive Summary of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD guidelines identify four stages of COPD severity based on post-bronchodilator FEV1 Stage 1 (Mild = FEV1 ge 80 predicted) Stage 2 (Moderate = 50 le FEV1 lt 80 predicted) Stage 3 (Severe = 30 predicted le FEV1 lt 50 predicted) and Stage 4 (Very Severe = FEV1 lt 30 predicted or FEV1 lt 50 predicted plus the presence of chronic respiratory failure)11 The American Thoracic




SocietyEuropean Respiratory Society (ATSERS) Guidelines include a 5 th category namely ldquoAt Riskrdquo which is based on FEV1 and risk factors including smoking or exposure to pollutants with cough sputum or dyspnea or a family history of respiratory disease12

Bronchodilator medications are central to the symptomatic management of COPD13141516 They improve emptying of the lungs tend to reduce dynamic hyperinflation at rest and during exercise and improve exercise performance17 They are given either on an as-needed basis for relief of persistent or worsening symptoms or on a regular basis to prevent or reduce symptoms Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting agents18 Combining bronchodilators may improve efficacy and decrease the risk of side effects as compared to maximizing the dose of a single bronchodilator19

The GOLD guidelines recommend a stepwise treatment plan for COPD based on disease severity20 Bronchodilator medications are central to symptom management in COPD For mild COPD a short-acting bronchodilator used on an as-needed basis is recommended For moderate and severe COPD regular use of one or more long-acting bronchodilators is recommended Long-acting inhaled bronchodilators are more effective and convenient than treatment with short-acting inhaled bronchodilators but there is insufficient evidence to recommend one long-acting agent over another The choice between a beta2 agonist anticholinergic theophylline or combination therapy depends on individual response in terms of symptom relief and adverse effects

In 2009 the updated GOLD guidelines were released and reiterated that beta2 agonist bronchodilators are among the principal treatments for symptomatic management of COPD21 The guidelines state that patient care should be based on level of disease severity and clinical symptoms The following medications are identified based on the likely order of introduction in treatment short-acting beta agonists long-acting beta agonists short-acting anticholinergics long-acting anticholinergics combination short-acting beta agonist plus anticholinergic in one inhaler methylxanthines inhaled glucocorticoids combination long-acting beta agonists plus glucocorticoids in one inhaler and systemic glucocorticoids

The American Thoracic Society (ATS) and European Respiratory Society (ERS) 2004 joint Standards for the Diagnosis and Management of COPD also recommend a similar stepwise treatment22 For intermittent symptoms an as-needed short-acting bronchodilator (beta2 agonist or anticholinergic) is recommended For persistent symptoms regular use of either a long-acting bronchodilator or a short-acting bronchodilator used four times daily in addition to an as-needed agent (beta2 agonist) is recommended If response to these measures is inadequate consider an alternative class of bronchodilator or combination therapy In addition these guidelines state that combining short-acting agents (albuterolipratropium) produces a greater change in spirometry over three months than either agent alone Combining long-acting inhaled beta-agonists and ipratropium leads to fewer exacerbations than either drug alone23

Medications for COPD currently available can reduce or abolish symptoms increase exercise capacity reduce the number and severity of exacerbations and improve health status At present no treatment is shown to modify the rate of decline in lung function24 Included in this review is a new oral agent roflumilast (Daliresp) which was FDA-approved in February 2011 as a treatment option in COPD management25




PHARMACOLOGY

The anticholinergic agents ipratropium (Atrovent) and tiotropium (Spiriva) antagonize the action of acetylcholine released from the vagus nerve Inhibition of the muscarinic receptors blocks the cholinergic neurotransmission causing bronchodilation

Tiotropium has similar affinity to the muscarinic receptor subtypes M1 to M5 Affinity to these receptors is six- to 20-fold greater than ipratropium In the airways tiotropium exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle Tiotropium dissociates rapidly from M2 receptors (blockade of the specific M2 receptor causes an increase in the release of acetylcholine which is an unwanted effect) but slowly from M1 and M3 receptors resulting in prolonged bronchodilation26

Roflumilast (Daliresp) and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4) This action leads to the accumulation of accumulation of cyclic adenosine monophosphate (cyclic AMP) in lung tissue The specific mechanism by which roflumilast exerts its therapeutic action in patients with COPD still is not well-defined27

PHARMACOKINETICS

Drug Onset of Action

15 percent or more increase in FEV1 (hours)

Time to Peak FEV1 (hours)

Duration of Action (hours)

albuterolipratropium inhalation solution (Duoneb)28

nr 15 43 - 5

albuterolipratropium MDI (Combivent)29

025 1 4 - 5

ipratropium inhalation solution (Atrovent)30

025 - 05 1 - 2 4 - 5 up to 7 - 8 in some

patients

ipratropium inhalation aerosol MDI (Atrovent HFA)31

025 1 - 2 2 - 4

tiotropium inhalation powder (Spiriva)32

05

(13 percent increase in FEV1) 1-4 24

nr = not reported

Bronchodilation following inhalation of these agents is a local site-specific effect It is important to note that roflumilast (Daliresp) is not a bronchodilator33

Although much of an administered dose of ipratropium (Atrovent) and tiotropium (Spiriva) is swallowed since they are quaternary amines minimal drug is absorbed from the gastrointestinal (GI) tract is expected Ipratropium is poorly absorbed from the lungs while tiotropium is highly bioavailable from the lung surface (195 percent absolute bioavailability)3435

Fourteen percent of an inhaled dose of tiotropium is excreted unchanged in the urine Renal impairment is associated with increased tiotropium concentrations after dry powder inhalation Approximately 25 percent of an absorbed tiotropium dose is metabolized via the cytochrome P450




system Inhibitors of CYP450 3A4 or 2D6 such as ketoconazole or quinidine may impact tiotropium metabolism36

The terminal elimination half-life of tiotropium is between five and six days and after once daily inhalation by COPD patients steady state was reached after two to three weeks37

The absolute bioavailability of roflumilast following a 500 microgram oral dose is approximately 80 percent Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99 percent and 97 percent respectively Following an oral dose the median plasma half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours respectively Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately four days for roflumilast and six days for roflumilast N-oxide following once daily dosing38

CONTRAINDICATIONSWARNINGS39404142434445

Patients with a history of hypersensitivity to atropine or any of its derivatives (eg ipratropium) should not use any of these products

Albuterolipratropium MDI (Combivent) is contraindicated in patients with a history of hypersensitivity to soy lecithin or related food products such as soybean or peanut

Tiotropium inhalation powder (Spiriva) is not indicated for the initial treatment of acute episodes of bronchospasm eg rescue therapy In addition immediate hypersensitivity reactions including angioedema may occur after administration If such a reaction occurs therapy should be stopped at once and alternative treatments should be considered

Roflumilast (Daliresp) is contraindicated for use in patients with moderate to severe liver impairment (Child-Pugh B or C)

Inhaled medicines may cause paradoxical bronchospasm which may be life-threatening If this occurs treatment with any of these products should be stopped and other alternatives considered

DRUG INTERACTIONS46474849505152

Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants should be used cautiously with albuterol-containing products like albuterolipratropium inhalation solution (Duoneb) and albuterolipratropium MDI (Combivent) due to the potentiation of cardiovascular effects A two-week discontinuation period of the MAO inhibitors and tricyclic antidepressants is suggested prior to initiating therapy with an albuterol-containing product

Use with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and CYP1A2 (eg erythromycin ketoconazole fluvoxamine cimetidine) will increase roflumilast (Daliresp) systemic exposure and may result in increased adverse reactions The risk of such concurrent use should be weighed carefully against benefit




ADVERSE EFFECTS

Drug Dry Mouth Head-ache Nausea Vomiting

Nervousness Palpitations

Chest Pain Tremor

albuterol ipratropium inhalation solution (Duoneb)53

nr nr 14 nr 26 nr

albuterol ipratropium MDI (Combivent)54

le 2 56 le 2 lt 2 03 lt 2


32 64 41 05 reported 09

ipratropium inhalation aerosol MDI (Atrovent HFA)

56

2-4 6-7 4 nr reported nr

roflumilast (Daliresp)57 nr 44 47 nr reported 1 - 2

tiotropium inhalation powder DPI (Spiriva)58

12-16 nr 1-4 nr 5-7 nr

Adverse effects are reported as a percentage Adverse effects data are obtained from package inserts and are not meant to be comparative or all-inclusive nr = not reported

The most common adverse event reported with tiotropium was dry mouth (16 percent) Other reports of adverse events with tiotropium are consistent with anticholinergic effects including constipation (four percent) blurred vision and new onset or worsening of glaucoma (percentages not reported) and urinary retention or difficulty (less than one percent)

In one trial that enrolled 198 COPD patients the number of patients with changes from baseline-corrected QT interval of 30 ndash 60 msec was higher in the tiotropium-treated group (range 16 to 20 percent) as compared to the placebo group (range one to 12 percent) depending on QT correction method used Other clinical studies did not detect a drug effect on QTc intervals59

A FDA MedWatch was issued on March 19 2008 related to an ongoing safety review of tiotropium and its potential to increase the risk of stroke in patients60 The information is based on data submitted by the manufacturer Boehringer Ingelheim from a pooled analysis of 29 placebo-controlled trials with 13500 patients with COPD The preliminary estimate of eight strokes per 1000 patients treated annually with tiotropium is higher than the six strokes per 1000 patients treated annually with placebo However on January 14 2010 the FDA completed its review and issued a statement that the available data do not support the association between Spiriva use and an increase risk for stroke myocardial infarction or death from a cardiovascular event Healthcare professionals are recommended to continue to prescribe Spiriva as directed by the prescribing information

The two most common adverse events reported with roflumilast were diarrhea (95 percent) and weight loss (75 percent)61

Monitoring

Anticholinergic drugs may worsen symptoms associated with narrow-angle glaucoma prostatic hyperplasia or bladder neck obstruction




Tiotropium is a predominantly renally excreted drug Patients with moderate-to-severe renal impairment (creatinine clearance less or equal to 50 mL per minute) should be monitored closely 62

Roflumilast has been associated with decreased weight so patients using this drug should have their weight monitored regularly If unexplained or clinically significant weight loss occurs an evaluation should be conducted and discontinuation of the drug should be considered63

SPECIAL POPULATIONS64656667686970

Pediatrics

COPD is a disease that does not normally occur in children Safety and effectiveness of ipratropium (Atrovent) albuterolipratropium MDI (Combivent) albuterolipratropium inhalation solution (Duoneb) roflumilast (Daliresp) and tiotropium DPI (Spiriva) in pediatric patients have not been established

Pregnancy

Albuterol albuterolipratropium MDI albuterolipratropium inhalation solution roflumilast and tiotropium are Pregnancy Category C Ipratropium is Category B

Other considerations ndash renal hepatic race etc

The pharmacokinetics of albuterolipratropium (Combivent) have not been studied in patients with renal insufficiency hepatic insufficiency or the elderly

The pharmacokinetics of ipratropium as not been studied in patients with renal or hepatic insufficiency

Since tiotropium is predominantly renally excreted renal impairment was associated with increased plasma drug concentrations and reduced drug clearance Patients with moderate to severe renal impairment (creatinine clearance of le50 mLmin) should be monitored closely for anticholinergic side effects when treated with tiotropium

An eight-week randomized double-blind placebo-controlled trial was conducted in 166 African-Americans with COPD to determine the efficacy of once daily inhaled tiotropium versus placebo71 The primary efficacy endpoint was the FEV1 AUC (0-3) after eight weeks of therapy A total of 160 patients were eligible for efficacy evaluation At the end of the study period the tiotropium group (n=78) had a FEV1 AUC (0-3) of 180 mL greater than the placebo group (n=82 plt00001) There were no significant differences in use of rescue medications between the two groups Also there were no patients in the tiotropium group who experienced a COPD exacerbation while there were 12 patients in the placebo group who did This study was sponsored and conducted by the manufacturer of tiotropium (Spiriva)

No dosage adjustment of roflumilast is necessary in patients with renal impairment Roflumilast is not recommended for use in patients with moderate to severe liver impairment (Child-Pugh B or C)




DOSAGES

Drug Adult Dose Availability

albuterol sulfate ipratropium bromide inhalation solution (Duoneb )72

3 mL four times daily (up to two additional 3 mL doses per day)

3 mg 05 mg per 3 mL

albuterolipratropium bromide MDI

(Combivent )73

Two inhalations four times daily (do not exceed 12 inhalations in 24 hours)

90 mcg 18 mcg per actuation

ipratropium bromide inhalation solution (Atrovent)74

25 mL three to four times daily 500 mcg per 25 mL



17 mcg per actuation

roflumilast (Daliresp)76

One tablet (500 micrograms) daily with or without food

Tablets 500 mcg


Handihaler )77 One inhalation daily 18 mcg per capsule



An FDA Public Health Advisory was issued in March 2008 to highlight the correct use of tiotropium (Spiriva) capsules which are to be used in the Handihaler device These capsules should not be swallowed78

CLINICAL TRIALS

Search Strategy

Articles were identified through searches performed on PubMed and review of information sent by manufacturers Search strategy included the FDA-approved use of all drugs in this class Randomized controlled comparative trials are considered the most relevant in this category Studies included for analysis in the review were published in English performed with human participants and randomly allocated participants to comparison groups In addition studies must contain clearly stated predetermined outcome measure(s) of known or probable clinical importance use data analysis techniques consistent with the study question and include follow-up (endpoint assessment) of at least 80 percent of participants entering the investigation Despite some inherent bias found in all studies including those sponsored andor funded by pharmaceutical manufacturers the studies in this therapeutic class review were determined to have results or conclusions that do not suggest systematic error in their experimental study design While the potential influence of manufacturer sponsorshipfunding must be considered the studies in this review have also been evaluated for validity and importance

albuterol MDI (Proventil Ventolin) + ipratropium MDI (Atrovent) versus formoterol DPI (Foradil) + ipratropium MDI (Atrovent)

A large randomized double-blind double-dummy two-period crossover study of 172 patients with COPD investigated the effects of the addition of either formoterol or albuterol to ipratropium in patients whose symptoms were not optimally controlled by ipratropium alone79 In addition to ipratropium MDI 40 mcg four times daily patients received in random order formoterol DPI 12 mcg




twice daily for three weeks followed by albuterol MDI 200 mcg four times daily for three weeks or vice versa Morning peak expiratory flow rate (PEFR) and FEV1 were significantly better with the formoterol-ipratropium combination than with the albuterol-ipratropium combination (p=00003 and plt00001 for PEFR and FEV1 respectively) Similar findings were noted for FVC On average all mean individual symptom scores were lower for patients receiving the formoterol-ipratropium combination than for those receiving the albuterol-ipratropium combination (p=00042) There were no significant differences between the formoterol and albuterol groups in mean percentage of days with no rescue drug (723 and 688 percent respectively) the number of patients with no COPD exacerbations (346 and 308 percent respectively) or the percentage of patients experiencing bad days during the trial (65 and 69 percent respectively)

roflumilast (Daliresp) versus placebo

The efficacy and safety of roflumilast in COPD was evaluated in eight randomized double-blind controlled parallel group clinical trials in 9394 adult patients (4425 receiving roflumilast 500 mcg) who were 40 years of age and older with COPD80 Of the eight trials two were placebo-controlled dose selection trials (Trials 1 and 2) of six months duration that evaluated the efficacy of roflumilast 250 mcg and 500 mcg once daily four were placebo-controlled one-year trials (Trials 3 4 5 and 6) primarily designed to evaluate the efficacy of roflumilast on COPD exacerbations and two were six-month efficacy trials (Trials 7 and 8) which assessed the effect of roflumilast as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic agent No trials have been conducted to assess the effects of roflumilast on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid

tiotropium (Spiriva) versus placebo

The Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a large randomized double-blind placebo-controlled trial that compared four years of therapy with either tiotropium or placebo in 5993 patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs81 The patients were at least 40 years of age with an FEV1 of 70 percent or less after bronchodilation and a ratio of FEV1 to FVC of 70 percent or less The objective of the study was to determine whether treatment with tiotropium 18 mcg reduced the rate of decline of FEV1 over time in patients with COPD The two co-primary end points were the yearly rate of decline in the mean FEV1 before the use of a study drug and short-acting bronchodilators in the morning (pre-bronchodilator) and after the use of a study drug (post-bronchodilator) from day 30 (steady state) until completion of double-blind treatment Secondary endpoints included measures of rates of mean decline for both FVC and slow vital capacity (SVC) health-related quality of life as measured by the total score on St Georges Respiratory Questionnaire (SGRQ) exacerbations of COPD and mortality Patients were randomly assigned to the tiotropium group (n=2987) or to the placebo group (n=3006) Mean absolute improvements in FEV1 in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 mL before bronchodilation and from 47 to 65 mL after bronchodilation) as compared with the placebo group (plt0001) After day 30 the differences between the two groups in the rate of decline in the mean FEV1 at any time point were not significant The mean absolute total score on the SGRQ was lower indicating improvement in the tiotropium group compared with the placebo group at each time point throughout the four-year period (plt0001) At four years and 30 days tiotropium treatment was associated with a reduction in the risks of




exacerbations related hospitalizations and respiratory failure but tiotropium did not significantly reduce the rate of decline in FEV1

In a subgroup analysis of the UPLIFT trial data from 2739 participants diagnosed with COPD (GOLD stage II) were examined82 The tiotropium group had a statistically insignificant lower decline of pre-bronchodilator FEV1 than the control group (35 mL per year versus 37 mL per year p=038) and lower post-bronchodilator FEV1 (43 mL per year versus 49 mL per year p=0024) SGRQ scores were lower in tiotropium group than the control group (ple0006 for all time points) indicating a statistically significant improved health status Mean number of exacerbations was lower in the tiotropium group than the control group (056 per patient-year versus 070 per patient-year plt00001) The results of this subgroup analysis provided further support for the rationale of starting a long-acting anticholinergic in patients with moderate COPD

tiotropium (Spiriva) versus albuterolipratropium MDI (Combivent)

A parallel group double-blind double-dummy randomized controlled trial was conducted in 676 patients with moderate to very severe stable COPD (mean FEV1 of 39 percent predicted) over an 84 day period to determine if patients already receiving albuterolipratropium combination four times daily could use tiotropium once daily as a potential alternative83 Patients were randomized to receive either tiotropium 18 mcg each morning or continue with albuterol 206 mcgipratropium 26 mcg using two actuations four times daily A six-hour spirometry assessment was conducted on study days one 22 and 84 In terms of primary outcomes mean trough FEV1 at 84 days was larger in the tiotropium arm compared to the combination arm (difference=86 mL 95 CI 49 to 123 mL plt00001) However the six hour spirometry assessments during the trial only confirmed non-inferiority of the two treatments (plt00001) and did not show superiority of tiotropium to the combination (p=037) Lower respiratory adverse events were reported in 40 tiotropium patients compared to 52 patients receiving the combination Otherwise safety reporting was similar for the two groups The authors concluded that patients previously maintained on albuterolipratropium combination taken four times daily can be switched to tiotropium once daily with the reasonable expectation of at least equivalent bronchodilation during daytime hours

tiotropium (Spiriva) versus ipratropium (Atrovent)

The Dutch Tiotropium Group evaluated and compared the efficacy and safety of tiotropium and ipratropium during long-term treatment of patients with stable COPD84 Two-hundred eighty-eight patients with mean age 65 years and mean FEV1 41 percent of predicted value participated in a 14-center double-blind double-dummy parallel group study Patients were randomized to receive either tiotropium 18 mcg once daily from a dry powder inhaler (HandiHaler two thirds of patients) or ipratropium 40 mcg four times daily from a metered dose inhaler (one third of patients) for 13 weeks Outcome measures were lung function daily records of PEF and the use of concomitant albuterol During treatment tiotropium achieved a significantly greater improvement than ipratropium in trough average and peak FEV1 levels trough and average FVC levels and weekly mean morning and evening PEF The use of concomitant albuterol was also significantly lower in the tiotropium group (plt005) The only drug related adverse event was dry mouth (tiotropium 147 percent versus ipratropium 103 percent)

Two one-year randomized double-blind double-dummy studies evaluated tiotropium 18 mcg once daily (n=356) with ipratropium 40 mcg four times daily (n=179)85 Mean baseline FEV1 values were 419




percent of predicted value for tiotropium and 394 percent of predicted value for ipratropium Trough FEV1 at one year improved by 012 +- 001 L with tiotropium and declined by 003 +- 002 L with ipratropium (plt0001) Tiotropium reduced the number of exacerbations by 24 percent (plt001) increased time to first exacerbation (plt001) and the time to first hospitalization for a COPD exacerbation (plt005) compared with ipratropium Apart from an increased incidence of dry mouth in the tiotropium group adverse events were similar between treatments

tiotropium (Spiriva) versus salmeterol (Serevent)

A six-month randomized placebo-controlled double-blind double-dummy parallel-group study in 623 patients (tiotropium n=209 salmeterol n=213 and placebo n=201) evaluated tiotropium 18 mcg once daily via dry-powder inhaler compared with salmeterol 50 mcg twice daily via metered dose inhaler The study was conducted in patients with a baseline mean FEV1 40 percent of predicted value and a mean age of 65 years86 Compared with placebo treatment the mean predose morning FEV1 following six months of therapy increased significantly more for the tiotropium group (014 L) than the salmeterol group (009 L) (plt001) The difference between tiotropium and salmeterol was statistically significant (005 L plt001) At study end trough FVC had improved significantly above placebo at 025 L for tiotropium (plt0001) and 013 L for salmeterol (plt0001) The difference between tiotropium and salmeterol was 011 L (plt001) Both active drugs significantly reduced the need for rescue albuterol Tiotropium patients also achieved meaningful changes in health related quality of life compared to salmeterol patients

Patients with COPD (tiotropium n=402 salmeterol n=405 placebo n=400) were enrolled in two six-month randomized placebo controlled double-blind double-dummy studies of tiotropium 18 mcg once daily via HandiHaler or salmeterol 50 mcg twice daily via a metered dose inhaler87 The two trials were combined for analysis of health outcomes consisting of exacerbations health resource use dyspnea (assessed by the transitional dyspnea index TDI) health-related quality of life (assessed by St Georges Respiratory Questionnaire [SGRQ]) and spirometry Compared with placebo tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation Fewer COPD exacerbations per patient year occurred in the tiotropium group (107 eventsyear) than in the salmeterol group (123 eventsyear p=0222) or in the placebo group (149 eventsyear plt005) The tiotropium group had 010 hospital admissions per patient year for COPD exacerbations compared with 017 for salmeterol and 015 for placebo (p=NS) SGRQ total scores improved by 42 28 and 15 units during the six-month trial for the tiotropium salmeterol and placebo groups respectively (plt001 tiotropium versus placebo) Compared with placebo TDI focal score improved in both the tiotropium group (11 units plt0001) and the salmeterol group (07 units plt005) The difference between tiotropium and salmeterol was not significant (p=017)

tiotropium (Spiriva) + placebo versus tiotropium (Spiriva) + salmeterol (Serevent) OR fluticasonesalmeterol (Advairreg)

A randomized double-blind placebo-controlled trial was conducted in Canada with 449 patients with moderate to severe COPD who had one year of treatment with tiotropium plus placebo tiotropium plus salmeterol or tiotropium plus fluticasonesalmeterol88 The proportion of patients in the tiotropium plus placebo group who had episodes of an exacerbation (628 percent) was not different from that in the tiotropium plus salmeterol group (648 percent [95 CI ndash128 to 88]) or in the tiotropium plus fluticasonesalmeterol group (60 percent [95 CI ndash82 to 138 percentage points])




Tiotropium plus fluticasonesalmeterol improved lung function as measured by FEV1 (p=0049) and disease-specific quality of life (p=001) reduced the number of hospitalizations for COPD exacerbation

(incidence rate ratio 053 [95 CI 033 to 086]) as well as all-cause hospitalizations (incidence rate ratio 067 [95 CI 045 to 099]) compared with tiotropium plus placebo In contrast tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo It is noteworthy that more than 40 percent of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely and many crossed over to treatment with open-label inhaled corticosteroids or long-acting beta-agonists The authors concluded that the addition of fluticasonesalmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function quality of life and hospitalization rates in patients with moderate to severe COPD

tiotropium (Spiriva) versus tiotropium (Spiriva) + formoterol (Foradil)

In a 12-week active-controlled double-blind multicenter trial a total of 255 subjects with COPD were randomized to either a combination of formoterol 12 mcg twice daily plus tiotropium 18 mcg once daily in the morning or monotherapy with tiotropium 18 mcg once daily in the morning 89 The primary efficacy variable was the area under the curve for forced expiratory volume in one second measured zero to four hours after the morning dosing (FEV1 AUC(0-4h)) Significantly greater improvements in the FEV1 AUC(0-4h) were seen with formoterol plus tiotropium versus tiotropium alone at all time points At endpoint FEV1 AUC(0-4h) increased 340 mL with formoterol plus tiotropium versus 170 mL with tiotropium alone (plt0001) Improvements in trough FEV1 with formoterol plus tiotropium versus tiotropium alone were 180 mL and 100 mL respectively (plt001) Significantly greater reductions from baseline in symptom scores (plt005) and daytime albuterol use (plt004) were seen at endpoint with combination formoterol plus tiotropium versus tiotropium monotherapy Both treatments were well tolerated

META-ANALYSES

A 2008 meta-analysis of 17 randomized controlled trials of 14783 patients was conducted to ascertain the cardiovascular risks including cardiovascular death myocardial infarction (MI) and stroke of inhaled anticholinergics (tiotropium or ipratropium bromide) versus control therapy (inhaled salmeterol inhaled salmeterolfluticasone inhaled albuterol or placebo)90 The study selection included trials of at least 30 days duration and reported on cardiovascular events The primary outcome was a composite of cardiovascular death MI or stroke The secondary outcome was all-cause mortality The authors state that cardiovascular death is a more frequent cause of death in patients with COPD than respiratory causes Based on the results inhaled anticholinergics significantly increased the risk of the composite outcome of cardiovascular death MI or stroke (18 percent versus 12 percent for control plt0001) Further delineation for individual primary outcomes were also assessed and showed inhaled anticholinergics significantly increased the risk of MI (12 percent versus 08 percent p=003) based on eleven trials involving 10598 patients Risk of cardiovascular death was significantly increased by inhaled anticholinergics (09 percent versus 05 percent p=0008) in twelve trials of 12376 patients On the other hand inhaled anticholinergics did not significantly increase the risk of stroke (05 percent versus 04 percent for control p=020) Inhaled anticholinergics also did not significantly increase the risk of all-cause mortality (2 percent versus 16 percent p=006) Important to note in the meta-analysis is that many of the trials included were small and short-term none of them were specifically designed to monitor risk of cardiovascular events and some of the reporting of




cardiovascular outcomes may have been incomplete Further prospective studies that are adequately powered are needed to assess the cardiovascular safety of the inhaled anticholinergics In the meantime the risks of adverse events (eg MI or cardiovascular death) versus benefits of symptomatic improvement (eg increase in exercise capacity reduced COPD exacerbations and hospitalizations and improved dyspnea) must be weighed when using the inhaled anticholinergics Unfortunately alternative therapeutic options are limited for patients with COPD due to their differing adverse effect profiles

Results from a systematic search including studies from MEDLINE and the Cochrane databases between 1966 and March 2007 on inhaled therapies and disease management were used to determine the effectiveness of management strategies for COPD (including inhaled therapies) in regards to exacerbations hospitalization and deaths and adverse effects91 Treatment was recommended for patients with stable COPD who have respiratory symptoms and FEV1lt60 Treatment should consist of one of the following long-acting inhaled beta-agonist long-acting inhaled anticholinergic or inhaled corticosteroid There was insufficient documentation to recommend one monotherapy over another since they had similar effectiveness although different adverse effects reductions in deaths and hospitalizations were observed Studies of combination therapies do not consistently show benefits of combination therapy over monotherapy

More questions will be generated as a result of a meta-analysis of 22 randomized double-blind placebo or active-controlled trials with 15276 patients92 The meta-analysis evaluated the safety and efficacy of anticholinergics (ipratropium and tiotropium) and beta2 agonists (albuterol metaproterenol formoterol and salmeterol) in COPD Anticholinergics significantly reduced severe COPD exacerbations compared to placebo as well as reduced respiratory deaths On the contrary beta2 agonists did not affect severe COPD exacerbations and actually increased the rate of respiratory deaths compared with placebo

SUMMARY

COPD is categorized in Stages I (mild) II (moderate) III (severe) and IV (very severe) Treatment initiation may begin with use of as-needed short-acting bronchodilators followed by routine long-acting bronchodilators inhaled corticosteroids long-term oxygen therapy and even surgery Regular use of long-acting beta agonists or short- or long-acting anticholinergics has been shown to improve health status

Albuterol is available in combination with ipratropium in both a MDI (Combivent) and as inhalation solution (Duoneb) for the treatment of COPD The combination MDI may be beneficial in reducing the number of puffs per day required as compared to treatment with the individual components

The two anticholinergic options in this class are ipratropium (Atrovent) and tiotropium (Spiriva) The long-acting anticholinergic agent tiotropium is dosed once daily and has a duration of action greater than 24 hours Both agents have been shown to improve bronchodilation dyspnea exacerbation rates and health-related quality of life Adverse effects are limited primarily to dry mouth that appears to resolve with continued use

Roflumilast (Daliresp) is the first and only selective phosphodiesterase-4 (PDE4) inhibitor to be FDA-approved in February 2011 as a treatment option in COPD management Unlike the other inhaled treatment options currently available roflumilast is an oral tablet formulation taken once daily Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm COPD




exacerbations are a leading cause of hospitalization and mortality The role of roflumilast in the comprehensive management of COPD remains to be fully elucidated93

REFERENCES

1 DuoNeb [package insert] Napa CA Dey March 2011

2 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 3 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 4 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 5 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 6 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 7 Rodriguez Roisen R Calverley P Rabe K et al Global strategy for the diagnosis management and prevention of chronic obstructive pulmonary disease executive summary updated 2009 Available from httpwwwgoldcopdorg Accessed June 6 2011 8 American Thoracic Society Statement Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Disease Am J Respir Crit

Care Med 1995 152577-5120 9 McCrorey D Brown c Gelfand S et al Management of Acute Exacerbations of COPD A Summary and Appraisal of Published Evidence Chest 2001 119(4)1190-1209 10 American Thoracic Society Statement Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Dis ease Am J Respir Crit Care Med 1995 152577-5120 11 Rodriguez Roisen R Calverley P Rabe K et al Global strategy for the diagnosis management and prevention of chronic obs tructive pulmonary disease executive summary updated 2009 Available from httpwwwgoldcopdorg Accessed June 6 2011 12 Qaseem A Snow V et al Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease A Clinical Practice Guidel ine from the American

College of Physicians Ann Int Med 2007 147(9)633-638 13 Vathenen AS Britton JR Ebden P et al High-dose inhaled albuterol in severe chronic airflow limitation Am Rev Respir Dis 1988 138850-855 14 Gross NJ Petty TL Friedman M et al Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease A three-center study Am Rev Respir Dis 1989 1391188-1191 15 Chrystyn H Mulley BA Peake MD Dose response relation to oral theophylline in severe chronic obstructive airways disease BMJ 1988 2971506-1510 16 Higgins BG Powell RM Cooper S et al Effect of salbutamol and ipratropium bromide on airway calibre and bronchial reactiv ity in asthma and chronic

bronchitis Eur Respir J 1991 4415-420 17 Wilson DH Wakefield MA Steven ID et al Sick of smoking evaluation of a targeted minimal smoking cessation intervention in general practice Med J Aust 1990 152518-521 18 The GOLD Guidelines Available at httpwwwgoldcopdorguploadsusersfilesGOLDReport_April112011pdf Accessed June 6 2011 19 The GOLD Guidelines Available at httpwwwgoldcopdorguploadsusersfilesGOLDReport_April112011pdf Accessed June 6 2011 20 The GOLD Guidelines Available at httpwwwgoldcopdorguploadsusersfilesGOLDReport_April112011pdf Accessed June 6 2011 21 The GOLD Guidelines Available at httpwwwgoldcopdorguploadsusersfilesGOLDReport_April112011pdf Accessed June 6 2011 22 Celli BR MacNee W et al Standards for the diagnosis and treatment of patients with COPD a summary of the ATSERS position paper Eur Respir J

2004 23 932ndash946 23 American Thoracic Society Standards for the Diagnosis and Management of Patients with Chronic Obstructive Pulmonary Disease Available at httpwwwthoracicorgclinicalcopd-guidelinesresourcescopddocpdf Accessed June 6 2011 24American Thoracic Society Standards for the Diagnosis and Management of Patients with Chronic Obstructive Pulmonary Disease Available at httpwwwthoracicorgclinicalcopd-guidelinesresourcescopddocpdf Accessed June 6 2011 25 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 26 PJ Barnes Tiotropium bromide Expert Opin Investig Drugs 2001 10733 27 Daliresp [package insert] St Louis MO Forest Laboratories February 2011

28 DuoNeb [package insert] Napa CA Dey March 2011 29 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 30 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 31 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 32 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 33 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 34 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 35 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009

36 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 37 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 38 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 39 DuoNeb [package insert] Napa CA Dey March 2011 40 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 41 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 42 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 43 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010

44 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 45 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 46 DuoNeb [package insert] Napa CA Dey March 2011 47 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011




48 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 49 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 50 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 51 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 52 Daliresp [package insert] St Louis MO Forest Laboratories February 2011

53 DuoNeb [package insert] Napa CA Dey March 2011 54 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 55 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 56 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 57 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 58 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 59 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 60 Available from httpwwwfdagovSafetyMedWatchSafetyInformationSafetyAlertsforHumanMedicalProductsucm095076htm Access ed June 6

2011 61 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 62 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 63 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 64 DuoNeb [package insert] Napa CA Dey March 2011 65 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 66 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002 67 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002

68 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 69 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 70 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 71 Criner G Sharafkhaneh A Player R et al Efficacy of tiotropium inhalation powder in African-American patients with chronic obstructive pulmonary disease COPD 2008 5(1) 35-41 72 DuoNeb [package insert] Napa CA Dey March 2011 73 Combivent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals April 2011 74 Atrovent [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals March 2002

75 Atrovent HFA [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2010 76 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 77 Spiriva [package insert] Ridgefield CT Boehringer Ingelheim Pharmaceuticals December 2009 78Available at httpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersDrugSafetyInformationforHeathcareProfessionalsPublicHealthAdvisoriesUCM051132 Accessed June 7 2011 79 DUrzo AD De Salvo MC Ramirez A et al In patients with COPD treatment with a combination of formoterol and ipratropium is more effective than a

combination of salbutamol and ipratropium Chest 2001 1191347-1356 80 Daliresp [package insert] St Louis MO Forest Laboratories February 2011 81 Tashkin D Celli B Senn S et al A 4-year trial of tiotropium in chronic obstructive pulmonary disease N Engl J Med 2008 359(15) 1543-54 82 Decramer M Celli B Kesten S et al Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmona ry disease (UPLIFT) a prespecified subgroup analysis of a randomized controlled trial Lancet 2009 374 1171-78 83 Niewoehner DE Lapidus R Cote S et al Therapeutic conversion of the combination of ipratropium and albuterol to tiotropium in patients with chronic obstructive pulmonary disease Pulm Pharmacol Ther 2009 22(6)587-92 84 van Noord JA Bantje TA Eland ME et al A randomized controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive

pulmonary disease The Dutch Tiotropium Study Group Thorax 2000 55(4)289-94 85 Vincken W van Noord JA Greefhorst AP et al Improved health outcomes in patients with COPD during 1 yrs treatment with t iotropium Eur Respir J 2002 19(2)209-16 86 Donohue JF van Noord JA Bateman ED et al A 6-month placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol Chest 2002 122(1)47-55 87 Brusasco V Hodder R Miravitlles M et al Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD Thorax 2003 58(5)399-404 88 Aaron SD Vandemheen KL Fergusson D et al Tiotropium in combination with placebo salmeterol or fluticaso ne-salmeterol for treatment of chronic

obstructive pulmonary disease a randomized trial Ann Intern Med 2007 146545-55 89 Tashkin DP Pearle J et al Formoterol and tiotropium compared with tiotropium alone for treatment of COPD J Chron Obstr Pulm Dis 2009 6(1)17-25 90 Singh S Loke Y Furberg C Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with COPD a systematic review and meta-analysis JAMA 2008 300(12)1439-50 91 Qaseem A Snow V et al Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease A Clinical Practice Guidel ine from the American College of Physicians Ann Int Med 2007 147(9)633-638 92 Salpeter SR Buckley NS Salpeter EE et al Metandashanalysis Anticholinergics but not beta-agonists reduce severe exacerbations and respiratory

mortality in COPD J Gen Intern Med 2006 21(10) 1011-19 93 Daliresp [package insert] St Louis MO Forest Laboratories February 2011




FDA-APPROVED INDICATIONS

Drug Manufacturer Indication(s)

albuterolipratropium inhalation solution

(Duoneb )1

generic For the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) in patients requiring more than one bronchodilator

albuterolipratropium MDI (Combivent )

2

Boehringer-Ingelheim For use in patients with COPD on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and require a second bronchodilator


solution (Atrovent )3

generic For maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema


aerosol MDI (Atrovent HFA)4

Boehringer-Ingelheim As a bronchodilator for maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema

roflumilast (DalirespTM)5 Forest Laboratories As a treatment to reduce the risk of COPD exacerbations in

patients with severe COPD associated with chronic bronchitis and a history of exacerbations


Handihaler )6

Boehringer-Ingelheim For the long-term once-daily maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema

To reduce COPD exacerbations



OVERVIEW

In the United States chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality7 COPD is a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema The airflow obstruction is generally progressive may be accompanied by airway hyperreactivity and may be partially reversible8

Although the precise distinctions between chronic bronchitis and emphysema are a subject of debate tradition holds that chronic bronchitis is responsible for 85 percent of COPD9 Patients with chronic bronchitis experience intermittent airway inflammation and excessive mucus production that leads to frequent prolonged episodes of productive cough In contrast 15 percent of patients with COPD suffer primarily from emphysema Emphysema is a disease in which destruction of the infrastructure of alveoli and distal airspaces and thus the portion of the lung that provides gas exchange and elastic recoil occurs10 The loss of alveolar walls results in decreased ventilation and a loss of the capillary network essential to perfusion

Both chronic bronchitis and emphysema predispose patients to a common constellation of symptoms and to a collection of derangements in respiratory function There are reductions in forced expiratory volume after one second (FEV1) forced vital capacity (FVC) FEV1FVC ratio and forced expiratory flow (FEF25-75) The 2009 revised Executive Summary of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD guidelines identify four stages of COPD severity based on post-bronchodilator FEV1 Stage 1 (Mild = FEV1 ge 80 predicted) Stage 2 (Moderate = 50 le FEV1 lt 80 predicted) Stage 3 (Severe = 30 predicted le FEV1 lt 50 predicted) and Stage 4 (Very Severe = FEV1 lt 30 predicted or FEV1 lt 50 predicted plus the presence of chronic respiratory failure)11 The American Thoracic













PHARMACOLOGY




PHARMACOKINETICS






nr 15 43 - 5


025 1 4 - 5


025 - 05 1 - 2 4 - 5 up to 7 - 8 in some

patients


025 1 - 2 2 - 4


05


nr = not reported






















ADVERSE EFFECTS



Chest Pain Tremor


nr nr 14 nr 26 nr


le 2 56 le 2 lt 2 03 lt 2


32 64 41 05 reported 09


56




12-16 nr 1-4 nr 5-7 nr






Monitoring








Pediatrics


Pregnancy











DOSAGES




3 mg 05 mg per 3 mL


(Combivent )73










Tablets 500 mcg






CLINICAL TRIALS

Search Strategy






































META-ANALYSES








SUMMARY









REFERENCES


































PHARMACOLOGY




PHARMACOKINETICS






nr 15 43 - 5


025 1 4 - 5


025 - 05 1 - 2 4 - 5 up to 7 - 8 in some

patients


025 1 - 2 2 - 4


05


nr = not reported






















ADVERSE EFFECTS



Chest Pain Tremor


nr nr 14 nr 26 nr


le 2 56 le 2 lt 2 03 lt 2


32 64 41 05 reported 09


56




12-16 nr 1-4 nr 5-7 nr






Monitoring








Pediatrics


Pregnancy











DOSAGES




3 mg 05 mg per 3 mL


(Combivent )73










Tablets 500 mcg






CLINICAL TRIALS

Search Strategy






































META-ANALYSES








SUMMARY









REFERENCES








































ADVERSE EFFECTS



Chest Pain Tremor


nr nr 14 nr 26 nr


le 2 56 le 2 lt 2 03 lt 2


32 64 41 05 reported 09


56




12-16 nr 1-4 nr 5-7 nr






Monitoring








Pediatrics


Pregnancy











DOSAGES




3 mg 05 mg per 3 mL


(Combivent )73










Tablets 500 mcg






CLINICAL TRIALS

Search Strategy






































META-ANALYSES








SUMMARY









REFERENCES




























Pediatrics


Pregnancy











DOSAGES




3 mg 05 mg per 3 mL


(Combivent )73










Tablets 500 mcg






CLINICAL TRIALS

Search Strategy






































META-ANALYSES








SUMMARY









REFERENCES

























DOSAGES




3 mg 05 mg per 3 mL


(Combivent )73










Tablets 500 mcg






CLINICAL TRIALS

Search Strategy






































META-ANALYSES








SUMMARY









REFERENCES
























































META-ANALYSES








SUMMARY









REFERENCES




























SUMMARY









REFERENCES


























REFERENCES






















bronchodilators, copd - nevada medicaid bronchodilators is more effective and convenient than...

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